Examining the role of macrolides and host immunity in combatting filarial parasites

Abstract

Macrocyclic lactones (MLs), specifically the avermectins and milbemycins, are known for their effectiveness against a broad spectrum of disease-causing nematodes and arthropods in humans and animals. In most nematodes, drugs in this class induce paralysis, resulting in starvation, impaired ability to remain associated with their anatomical environment, and death of all life stages. Initially, this was also thought to be the ML mode of action against filarial nematodes, but researchers have not been able to validate these characteristic effects of immobilization/starvation of MLs in vitro, even at higher doses than are possible in vivo. Relatively recently, ML receptor sites exclusively located proximate to the excretory-secretory (ES) apparatus were identified in Brugia malayi microfilaria and an ML-induced suppression of secretory protein release by B. malayi microfilariae was demonstrated in vitro. It is hypothesized here that suppression of these ES proteins prevents the filarial worm from interfering with the host’s complement cascade, reducing the ability of the parasite to evade the immune system. Live microfilariae and/or larvae, thus exposed, are attacked and presented to the host’s innate immune mechanisms and are ultimately killed by the immune response, not the ML drug. These live, exposed filarial worms stimulate development of innate, cellular and humoral immune responses that when properly stimulated, are capable of clearing all larvae or microfilariae present in the host, regardless of their individual sensitivity to MLs. Additional research in this area can be expected to improve our understanding of the relationships among filarial worms, MLs, and the host immune system, which likely would have implications in filarial disease management in humans and animals.

Dirofilaria immitis Microfilariae and Third-Stage Larvae Induce Canine NETosis Resulting in Different Types of Neutrophil Extracellular Traps

“…However, since evidence of resistance to this drug class was already reported in the USA ( 67 , 68 ), efficacious prevention of canine dirofilariosis might be endangered in future. In this context, a strong adherence of PMN to B. malayi microfilariae in the presence of low ivermectin concentration and enhanced microfilarial killing by PMN or peripheral blood mononuclear cells by ivermectin treatments has been reported ( 69 – 71 ). Interestingly, receptor sites for macrocyclic lactones are exclusively located proximate of the excretory–secretory (ES) apparatus, which is the main site of microfilarial protein release ( 72 ).…”

Brugia malayi infection in ferrets – A small mammal model of lymphatic filariasis

“…These results parallel what is observed in humans where individuals that are symptomatic typically have low levels of microfilaremia and high inflammatory cytokine responses to antigen whereas those that are asymptomatic microfilaremics typically are highly immunoregulated [ 15 – 21 ]. Because some antifilarial medications work with the immune system to enable parasite clearance [ 16 , 22 , 23 ], and because potential adverse effects of novel agents include inflammatory responses against dying adult worms, understanding whether the immune responses in the Brugia /ferret model parallel those in humans is important for determining whether this model will be a robust one for predicting effects of antifilarial medications in humans.…”

Identification of the complement 9‐binding protein in Setaria equina excretory‐secretory products

“…The combination of diethylcarbamazine citrate (the anti‐filarial drug) suppressed the actions of SeqES. Similarly, avermectins were found to suppress the actions of filarial ES to evade the host immune responses including the complement system . In the current study, the released protein in ES which binds to complement and inhibits its activation was identified.…”